Phosphorylation-dependent conformational transition of the cardiac specific N-extension of troponin I in cardiac troponin.

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dc.contributor.authorHowarth, JWen_AU
dc.contributor.authorMeller, Jen_AU
dc.contributor.authorSolaro, RJen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.contributor.authorRosevear, PRen_AU
dc.date.accessioned2008-04-28T02:14:24Zen_AU
dc.date.accessioned2010-04-30T05:02:46Zen_AU
dc.date.available2008-04-28T02:14:24Zen_AU
dc.date.available2010-04-30T05:02:46Zen_AU
dc.date.issued2007-10-26en_AU
dc.date.statistics2007-10en_AU
dc.description.abstractWe present here the solution structure for the bisphosphorylated form of the cardiac N-extension of troponin I (cTnI(1-32)), a region for which there are no previous high-resolution data. Using this structure, the X-ray crystal structure of the cardiac troponin core, and uniform density models of the troponin components derived from neutron contrast variation data, we built atomic models for troponin that show the conformational transition in cardiac troponin induced by bisphosphorylation. In the absence of phosphorylation, our NMR data and sequence analyses indicate a less structured cardiac N-extension with a propensity for a helical region surrounding the phosphorylation motif, followed by a helical C-terminal region (residues 25-30). In this conformation, TnI(1-32) interacts with the N-lobe of cardiac troponin C (cTnC) and thus is positioned to modulate myofilament Ca2+-sensitivity Bisphosphorylation at Ser23/24 extends the C-terminal helix (residues 21-30) which results in weakening interactions with the N-lobe of cTnC and a re-positioning of the acidic amino terminus of cTnI(1-32) for favorable interactions with basic regions, likely the inhibitory region of cTnI. An extended poly(L-proline)II helix between residues 11 and 19 serves as the rigid linker that aids in re-positioning the amino terminus of cTnI(1-32) upon bisphosphorylation at Ser23/24. We propose that it is these electrostatic interactions between the acidic amino terminus of cTnI(1-32) and the basic inhibitory region of troponin I that induces a bending of cThI at the end that interacts with cTnC. This model provides a molecular mechanism for the observed changes in cross-bridge kinetics upon TnI phosphorylation. © 2007, Elsevier Ltd.en_AU
dc.identifier.citationHowarth, J. W., Meller, J., Solaro, R. J., Trewhella, J., & Rosevear, P. R. (2007). Phosphorylation-dependent conformational transition of the cardiac specific N-extension of troponin I in cardiac troponin. Journal of Molecular Biology, 373(3), 706-722. doi:10.1016/j.jmb.2007.08.035en_AU
dc.identifier.govdoc1175en_AU
dc.identifier.issn0022-2836en_AU
dc.identifier.issue3en_AU
dc.identifier.journaltitleJournal of Molecular Biologyen_AU
dc.identifier.pagination706-722en_AU
dc.identifier.urihttp://dx.doi.org/10.1016/j.jmb.2007.08.035en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/1126en_AU
dc.identifier.volume373en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.subjectNuclear magnetic resonanceen_AU
dc.subjectPhosphorylationen_AU
dc.subjectProtonsen_AU
dc.subjectModulationen_AU
dc.subjectCrystal structureen_AU
dc.subjectAtomic modelsen_AU
dc.titlePhosphorylation-dependent conformational transition of the cardiac specific N-extension of troponin I in cardiac troponin.en_AU
dc.typeJournal Articleen_AU
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